PROJECT SUMMARY Training Plan: This proposal describes a mentored 5-year research training program for the development of an independent investigator in analgesic mechanisms. The Principal Investigator is an Instructor of Anaesthesia at Harvard Medical School (HMS) and a faculty anesthesiologist at Massachusetts General Hospital (MGH), with a background in cardiovascular physiology and anesthetic electrophysiology. His mentor, Dr. Emery N. Brown, is Warren M. Zapol Professor of Anaesthesia at HMS, Professor of Computational Neuroscience in the Dept. of Brain and Cognitive Sciences at the Massachusetts Institute of Technology (MIT), and Professor of Health Sciences and Technology at HMS and MIT. His Co-Mentor, Dr. Mao, is the Vice Chair for Research in the Department of Anesthesia, Critical Care and Pain Medicine at MGH and the Richard J. Kitz Professor of Anesthesia Research at HMS. He is a practicing board-certified anesthesiologist and Pain Medicine Specialist who currently directs both the Division of Pain as well as MGH's translational pain laboratory. With the Mentored Clinical Scientist Research Career Development Award, the Principal Investigator will acquire new knowledge and skills in chronic pain models, systems neuroscience and translational research study design sufficient to develop an independent research program. He will take courses in the Dept. of Brain and Cognitive Sciences at MIT, the Harvard School of Public Health and through the Harvard Catalyst and his research training will take place in laboratories at MGH and MIT. The long-term objective of this proposal is to prepare the Principal Investigator for a successful independent career studying analgesic mechanisms using a systems neuroscience approach. Research Plan: The treatment of chronic pain remains a significant public health problem, which is compounded by the epidemic of opioid addiction and related overdose deaths. Neural dopamine (DA) circuits may be a promising target to produce analgesia, while also preventing opioid-induced side effects such as nausea, respiratory depression and sedation, but their role in pain is poorly understood. Our preliminary studies demonstrate that ?-amphetamine is equipotent to morphine in abolishing thermal hyperalgesia in a mouse model of inflammatory chronic pain, and that selective activation of DA neurons in the periaqueductal gray (PAG) produces analgesia. The goal of this project is to elucidate the role of dopaminergic analgesic circuits on descending pain inhibition. Using a combination of pharmacological and selective neural circuit modulation techniques, we will probe the behavioral and analgesic properties of PAG dopamine circuits in clinically significant mouse models of inflammatory, neuropathic and cancer pain. Understanding how dopamine modulating agents relieve pain may lead to effective new pain treatments.